HLA Allele E*01:01 Is Associated with a Reduced Risk of EBV-Related Classical Hodgkin Lymphoma Independently of HLA-A*01/*02

Paloma Martín; Isabel Krsnik; Belen Navarro; Mariano Provencio; Juan F García; Carmen Bellas; Carlos Vilches; Natalia Gomez-Lozano

doi:10.1371/journal.pone.0135512

HLA Allele E01:01 Is Associated with a Reduced Risk of EBV-Related Classical Hodgkin Lymphoma Independently of HLA-A01/*02

PLoS One. 2015 Aug 11;10(8):e0135512. doi: 10.1371/journal.pone.0135512. eCollection 2015.

Authors

Paloma Martín¹, Isabel Krsnik², Belen Navarro², Mariano Provencio³, Juan F García⁴, Carmen Bellas¹, Carlos Vilches⁵, Natalia Gomez-Lozano⁶

Affiliations

¹ Group of Molecular Pathology, Instituto de Investigación Sanitaria Puerta de Hierro (IDIPHIM), Majadahonda, Spain.
² Department of Hematology, Instituto de Investigación Sanitaria Puerta de Hierro (IDIPHIM), Majadahonda, Spain.
³ Department of Oncology, Instituto de Investigación Sanitaria Puerta de Hierro (IDIPHIM), Majadahonda, Spain.
⁴ Department of Pathology, MD Anderson Cancer Center, Madrid, Spain.
⁵ Group of Immunogenetics and Histocompatibility, Instituto de Investigación Sanitaria Puerta de Hierro (IDIPHIM), Majadahonda, Spain.
⁶ Group of Immunity and lymphoproliferative diseases, Instituto de Investigación Sanitaria Puerta de Hierro (IDIPHIM), Majadahonda, Spain.

Abstract

Background: An inefficient immune response against Epstein-Barr virus (EBV) infection is related to the pathogenesis of a subgroup of classical Hodgkin lymphomas (cHL). Some EBV immune-evasion mechanisms target HLA presentation, including the non-classical HLA-E molecule. HLA-E can be recognized by T cells via the TCR, and it also regulates natural killer (NK) cell signaling through the inhibitory CD94/NKG2A receptor. Some evidences indicate that EBV-infected B-cells promote the proliferation of NK subsets bearing CD94/NKG2A, suggesting a relevant function of these cells in EBV control. Variations in CD94/NKG2A-HLA-E interactions could affect NK cell-mediated immunity and, consequently, play a role in EBV-driven transformation and lymphomagenesis. The two most common HLA-E alleles, E*01:01 and E*01:03, differ by a single amino acid change that modifies the molecule function. We hypothesized that the functional differences in these variants might participate in the pathogenicity of EBV.

Aim: We studied two series of cHL patients, both with EBV-positive and-negative cases, and a cohort of unrelated controls, to assess the impact of HLA-E variants on EBV-related cHL susceptibility.

Results: We found that the genotypes with at least one copy of E*01:01 (i.e., E*01:01 homozygous and heterozygous) were underrepresented among cHL patients from both series compared to controls (72.6% and 71.6% vs 83%, p = 0.001). After stratification by EBV status, we found low rates of E*01:01-carriers mainly among EBV-positive cases (67.6%). These reduced frequencies are seen independently of other factors such as age, gender, HLA-A*01 and HLA-A*02, HLA alleles positively and negatively associated with the disease (adjusted OR = 0.4, p = 0.001). Furthermore, alleles from both HLA loci exert a cumulative effect on EBV-associated cHL susceptibility.

Conclusions: These results indicate that E*01:01 is a novel protective genetic factor in EBV-associated cHL and support a role for HLA-E recognition on the control of EBV infection and lymphomagenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Alleles*
Case-Control Studies
Disease Susceptibility
Epistasis, Genetic
Epstein-Barr Virus Infections / complications*
Female
Genotype
HLA-A Antigens / genetics*
HLA-E Antigens
Herpesvirus 4, Human*
Histocompatibility Antigens Class I / genetics*
Hodgkin Disease / etiology*
Hodgkin Disease / pathology
Humans
Male
Middle Aged
Odds Ratio
Phenotype
Risk

Substances

HLA-A Antigens
Histocompatibility Antigens Class I

Grants and funding

This work was supported by Miguel Servet programs CP09/00182 (NGL) and CP08/00218 (PM) and the Spanish Cancer Network (RTICC RD 06/0020/0047) all from Instituto de Salud Carlos III (FEDER). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.